Substituted 5-(phenoxyalkyl)-3-phenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidines

ABSTRACT

Substituted 5-(phenoxyalkyl)-3-phenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidines, in which hydrogens of their benzene rings may be replaced by halogen, lower alkoxy, lower alkyl, nitro, acetamido and/or trifluoromethyl groups, are useful as antifungal agents.

BACKGROUND OF THE INVENTION

This invention pertains generally to substituted 2-methylisoxazolidinesand more specifically to substituted5-(phenoxyalkyl)-3-phenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidineswhich are useful as antifungal agents.

BRIEF SUMMARY OF THE INVENTION

In accordance with this invention there are provided compounds of theformula: ##STR1## and the pharmaceutically acceptable acid additionsalts thereof, in the form of their enantiomers or mixtures of theirenantiomers including diastereoisomeric pairs of such enantiomers,wherein;

a =1 or 2,

b =1 or 2,

R¹ is selected from hydrogen, lower alkyl, lower alkoxy, halogen, andcombinations thereof, provided that the ortho position is hydrogen,

R² is selected from hydrogen, lower alkyl, lower alkoxy, halogen,trifluoromethyl, nitro, acetamido, and combinations thereof, and

The alkyl moiety (CH₂)n represents a branched or unbranched chain wheren =1 to 8.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are useful as antifungal agents. Theyhave been shown to have activity against yeast and systemic mycoses anddermatophytes as determined by broth and agar testing techniques[McGinnis, M. R., Laboratory Handbook of Medical Mycology, AcademicPress, N.Y., N.Y. (1980)]. The compounds prepared in Examples 1-14,16-18 and 22-27 below were tested and found to have good to moderateinhibitory activity against a broad spectrum of organisms includingtrichophyton mentagrophytes, trichophyton tonsurans, trichophytonschoenleinii, epidermophyton floccosum and candida stellatoidea (minimuminhibitory concentration, MIC, of <0.2 to 70 ug/ml).

Because of the antifungal activity of the compounds of the inventionthey can be used, for example, in suitable liquid, semi-solid or solidcarriers in the form of solutions, emulsions, suspensions, dispersions,ointments, aerosols, soaps, detergents, and powders in amounts effectiveto combat systemic and dermatophylic fungal infections in warm bloodedanimals (1 to 20 percent active ingredient).

The compounds of this invention are those of the formula: ##STR2## andthe pharmaceutically acceptable acid addition salts thereof, in the formof their enantiomers or mixtures of their enantiomers includingdiastereoisomeric pairs of such enantiomers, wherein;

a =1 or 2,

b =1 or 2,

R¹ is selected from hydrogen, lower alkyl, lower alkoxy, halogen, andcombinations thereof, provided that the ortho position is hydrogen,

R² is selected from hydrogen, lower alkyl, lower alkoxy, halogen,trifluoromethyl, nitro, acetamido, and combinations thereof, and

The alkyl moiety (CH₂)n represents a branched or unbranched chain wheren =1 to 8.

By halogen is meant chlorine, bromine, fluorine and iodine with chlorineand fluorine being preferred. By lower alkyl and lower alkoxy is meantC₁ to C₄ which can be a branched or unbranched chain. Compounds havingortho substitution of the upper phenyl group were not prepared probablydue to steric hindrance.

The5-(phenoxyalkyl)-3-phenyl-3-(1H-imidazol-1-yl-methyl)-2-methylisoxazolidinesare obtained as mixtures of cis- and trans-diastereomers due to thepresence in the isoxazolidine ring of two asymmetric carbon atoms. Thediastereomeric mixture is conveniently separated by flash-chromatographyon silica gel using halogenated hydrocarbons (preferably dichloromethaneand chloroform), alkanols (preferably methanol and ethanol), ethylacetate and such as eluents. The eluents may be utilized alone or incombinations such as the ones comprised of 95-99% by volume halogenatedhydrocarbon and 1-5% by volume alkanol. The stereochemistry of the twoasymmetric carbon atoms in the isoxazolidine ring may be determined byconventional methods that include X-ray crystallography, nuclearmagnetic resonance spectroscopy, circular dichroism or optical rotatorydispersion. Both the cis and trans stereoisomers are resolvable intotheir optical enantiomers with (+) and (-) optical rotations by standardtechniques such as fractional recrystallization of the diastereomericsalts with optically active organic acids such as (+) and (-)-tartaricacid, (+) and (-)-dibenzoyltartaric acid and the like.

As illustrated in the following diagrams, the compounds can be preparedstarting with the reaction of 2-(1H-imidazol-1-yl)acetophenones 1 withN-methylhydroxylamine to give the corresponding nitrone derivatives 2which are the subject matter of our concurrently filed copendingapplication Ser. No. 900,856 entitled "α-Substituted KetonitroneDerivatives"whose disclosure is incorporated herein by reference. In onesynthesis scheme, the latter derivative is treated with an appropriateallyl phenyl ether compound 3 to provide a diastereomeric mixture of thedesired cis- and trans-substituted5-(phenoxymethyl)-3-phenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidinederivative 4. Alternatively, reaction of the nitrone compound 2 with anappropriate 1-(ω-alkenyloxy)benzene derivative (5) leads to thecorresponding diastereomeric mixture of cis- and trans-substituted5-[(ω-phenoxy)alkyl]-3-phenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidinecompound 6 (n>1). ##STR3##

The compounds of the invention are basic and thus can form salts withpharmaceutically acceptable inorganic and organic acids such as, forexample, acetic acid, maleic acid, malic acid, fumaric acid, succinicacid, succinamic acid, tartaric acid, citric acid, lactic acid,hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid,sulfuric acid and phosphoric acid.

The preparation of the compounds of the invention is further illustratedby the following synthesis of intermediates and in the Examples. Unlessotherwise indicated, n=1.

PREPARATION OF IMIDAZOLYLACETOPHENONES (1)

The imidazolylacetophenone compounds 1 are prepared according to knownprocedures, for example, (a) Godefroi et al., J. Medicinal Chem. 12, 784(1969) and (b) Nardi et al., J. Medicinal Chem. 24, 727 (1981).

The following imidazolyacetophenones 1 were synthesized:

(1) 2-(1H-imidazol-1-yl)acetophenone, mp 117°-119° C.,

(2) 2-(1H-imidazol-1-yl)-4'-chloroacetophenone 152°-156° C.,

(3) 2-(1H-imidazol-1-yl)-4'-methylacetophenone, mp 133°-137° C.,

(4) 2-(1H-imidazol-1-yl)-4'-methoxyacetophenone, mp 134°-137° C.,

(5) 2-(1H-imidazol)-1-yl)-4'-fluoroacetophenone, mp 150°-155° C.,

(6) 2-(1H-imidazol-1-yl)-3',4'-dichloroacetophenone, mp 124°-126° C.,

(7) 2-(1H-imidazol-1-yl)-4'-chloro-3'-methylacetophenone, mp 116°-118°C.,

(8) 2-(1H-imidazol-1-yl)-3'-methoxyacetophenone, mp 111°-113° C., and

(9) 2-(1H-imidazol-1-yl)-3'-methylacetophenone.

PREPARATION OF ALLYL PHENYL ETHER COMPOUNDS (3)

The allyl phenyl ether compounds 3 are made by standard procedures [(a)White et al., J. Am. Chem. Soc. 80, 3271 (1958), (b) Tarbell and Wilson,J. Am. Chem. Soc. 64, 1066 (1942), (c) Mirek, Zesz. Nauk Univ.Jagiellon, Pr. Chem., No 9, p. 77 (1964), and (c) McBee and Rapkin, J.Am. Chem. Soc. 73, 2375 (1951) ] from appropriately substituted phenolsand allyl bromide. The following allyl phenyl ether derivatives wereprepared:

(1) allyl 4-chlorophenyl ether, bp 55°-60° C. (0.05 Torr),

(2) allyl 4-methylphenyl ether, bp 45°-47° C. (0.3 Torr),

(3) allyl 4-methoxyphenyl ether, bp 65°-68° C. (0.2 Torr),

(4) allyl 4-acetamidophenyl ether, mp 90°-94° C.,

(5) allyl 2-nitrophenyl ether, bp 92°-99° C. (0.15 Torr),

(6) allyl 2,4-dichlorophenyl ether, bp 62°-65° C. (0.05 Torr),

(7) allyl 2,6-dichlorophenyl ether, bp 45°-50° C. (0.05 Torr),

(8) allyl 4-fluorophenyl ether, bp 35°-37° C. (0.025 Torr), and

(9) allyl 3-(trifluoromethyl)phenyl ether, bp 35°-37° C. (0.2 Torr).

The 1-(3-butenyloxy)-4-chlorobenzene (5, R² =4--Cl) was prepared by theprocedure of Rius-Alonso and Wain, Ann. Apl. Biol. 88, 299 (1978), aswere 4-chloro-1-(4-pentenyloxy)-benzene and4-fluoro-1-(4-pentenyloxy)benzene.

EXAMPLE 1 Preparation of5-(4-Chlorophenoxymethyl)-3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine(4, R¹ =R² =4--Cl)

A suspension of 2-(1H-imidazol-1-yl)-4'-chloroacetophenone (1, R¹=4--Cl) (19.90 g, 0.0902 mol), N-methylhydroxylamine hydrochloride(10.26 g, 0.123 mol) and sodium bicarbonate (10.37 g, 0.123 mol) in 200ml ethanol is refluxed for 27 hours, under a nitrogen atmosphere. Aftercooling to room temperature, the suspension is filtered and the solventis removed under reduced pressure. The residual orange-colored oil isdissolved in chloroform, filtered, and the solvent removed under reducedpressure. The oily residue (compound 2, R¹ =4--Cl) is taken up in 200 mlof toluene and 22.8 g (1.50 equivalent) of 4-chlorophenyl allyl ether(compound 3, R² =4--Cl) is added under a nitrogen atmosphere. Theresulting solution is refluxed for 42 hours, cooled to room temperatureand the solvent removed under reduced pressure. The residualdark-colored viscous oil which represents a cis- andtrans-diastereomeric mixture of compound 4 (R¹ =R² =4--Cl) isflash-chromatographed on neutral silica gel using chloroform andmethanol (in a 98:2 ratio by volume) as eluent. 18.64 g (49.4%) of thecis-isomer A is obtained by crystallization from ether. An analyticalsample is prepared by crystallization from ethyl acetate, mp 126°-132°C.

Anal. Calcd for C₂₁ H₂₁ Cl₂ N₃ O₂ : C, 60.30; H, 5.06; N, 10.04; Cl,16.95. Found: C, 60.36; H, 5.15; N. 9.97; Cl, 17.14.

The trans-isomer B (6.28 g, 16.6%) is obtained by crystallization fromisopropanol, mp 134°-137° C.

Anal. Calcd for C₂₁ H₂₁ Cl₂ N₃ O₂ : C, 60.30; H, 5.06; N, 10.04: Cl,16.95 Found: C, 60.36; H, 5.17; N, 9.97; Cl, 16.89.

The above preparation was repeated except that sodium acetate (20.18 g,0.246 mol) was used to prepare the nitrone intermediate in place ofsodium bicarbonate.

EXAMPLE 25-(4-Chlorophenoxymethyl)-3-(4-methoxyphenyl)-3-(1H-imidazol-1-ylmethyl-2-methylisoxazolidine(4, R¹ =4--OCH₃, R² =4--Cl)

The title compound 4 (R¹ =4--OCH₃, R² =4--Cl) was made by a proceduresimilar to that described in Example 1 by reacting2-(1H-imidazol-1-yl)-4'-methoxyacetophenone (1, R¹ =4--OCH₃) withN-methylhydroxylamine hydrochloride to form the corresponding nitronederivative 2 (R¹ =4--OCH₃), and treating the latter with 4-chlorophenylallyl ether (3, R² =4--Cl). The resulting cis- and trans-diastereomericmixture of compound 4 (R¹ =4--OCH₃, R² =4--Cl) was flash-chromatographedon neutral silica gel using a 98:2 by volume mixture of chloroform andmethanol as eluent.

Isomer A has a melting point of 130°-132° C. (ethyl acetate).

Anal. Calcd for C₂₂ H₂₄ ClN₃ O₃ : C, 63.84; H, 5.84: N, 10.15; Cl, 8.57.found: C, 63.91: H, 5.94; N, 10.21; Cl, 8.59.

Isomer B has a melting point of 36°-38° C. (ethyl acetate-hexane, in a4:1 ratio by volume).

EXAMPLE 35-(4-Chlorophenoxymethyl)-3-(4-methylphenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine(4, R¹ =4--CH₃, R² =4--Cl)

Compound 4 (R¹ =4--CH₃, R² =4--Cl) was prepared by a procedure similarto that described in Example 1 by reacting2-(1H-imidazol-1-yl)-4'-methylacetophenone (1, R¹ =4--CH₃) withN-methylhydroxylamine hydrochloride to form the corresponding nitronederivative 2 (R¹ =4--CH₃), and treating the latter with 4-chlorophenylallyl ether (3, R² =4--Cl). The resulting cis- and trans-diastereomericmixture of compound 4 (R¹ =4--CH₃, R² =4--Cl) was purified byflash-chromatography on neutral silica gel using a 97:3 by volumemixture of chloroform and methanol as eluent. The pure isomer A (4, R¹=4--CH₃, R² =4--Cl) has a melting point of 143°-145° C. (ethyl acetate).

Anal. Calcd for C₂₂ H₂₄ ClN₃ O₂ ; C, 66.41; H, 6.08; N, 10.56; Cl, 8.91.Found: C, 66.38; H, 6.09; N. 10.54; Cl, 8.91.

EXAMPLE 45-(4-Chlorophenoxymethyl)-3-(4-fluorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine(4, R¹ =4--F, R² =4--Cl)

Compound 4 (R¹ =4--F, R² =4--Cl) was made by a procedure similar to thatdescribed in Example 1 by reacting2-(1H-imidazol-1-yl)-4'-fluoroacetophenone (1, R¹ =4--F) withN-methyldroxylamine hydrochloride to form the corresponding nitronederivative 2 (R¹ =4--F), and treating the latter with 4-chlorophenylallyl ether (3, R² =4--Cl). The resulting cis- and trans-diastereomericmixture of compound 4 (R¹ =4--F, R² =4--Cl) was flash-chromatographed onneutral silica gel using a 98:2 by volume mixture of chloroform andmethanol as eluent.

Isomer A has a melting point of 125°-127° C. (ethyl acetate).

Anal. Calcd for C₂₁ H₂₁ ClFN₃ O₂ : C, 62.76; H, 5.27; N, 10.46; Cl,8.82. Found: C, 62.92; H, 5.33; N, 10.35; Cl, 8.78.

Isomer B has a melting point of 61°-65° C. (isopropanol).

Anal. Calcd for C₂₁ H₂₁ ClFN₃ O₂ : C, 62.76; H, 5.27; N, 10.46; Cl,8.82. Found: C, 62.68; H, 5.50: N, 10.36; Cl, 8.86.

EXAMPLE 55-(4-Chlorophenoxymethyl)-3-phenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine(4, R¹ =H, R² =4--Cl)

Compound 4 (R¹ =H, R² =4--Cl) was prepared by a procedure similar tothat described in Example 1 by reacting 2-(1H-imidazol-1-yl)acetophenone(1, R¹ =H) with N-methylhydroxylamine hydrochloride to form thecorresponding nitrone derivative 2 (R¹ =H), and treating the latter with4-chlorophenyl allyl ether (3, R² =4--Cl). The resulting cis- andtrans-diastereomeric mixture of compound 4 (R¹ =H, R² =4--Cl) wasflash-chromatographed on neutral silica gel using a 98:2 by volumemixture of chloroform and methanol as eluent.

Isomer A has a melting point of 140°-142° C. (ethyl acetate).

Anal. Calcd for C₂₁ H₂₂ ClN₃ O² : C, 65.71; H, 5.78; N, 10.95; Cl, 9.24.Found: C, 65.69; H, 5.84; N, 10.85; Cl, 9.57.

Isomer B has a melting point of 141°-143° C. (ethyl acetate).

EXAMPLE 65-(4-Chlorophenoxymethyl)-3-(3,4-dichlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine(4, R¹ =3,4--Cl₂, R² =4--Cl)

Compound 4 (R¹ =3,4--Cl₂, R² =4--Cl) was made by a procedure similar tothat described in Example 1 by reacting2-(1H-imidazol-1-yl)-3',4'-dichloroacetophenone (1, R¹ =3,4--Cl₂) withN-methylhydroxylamine hydrochloride to form the corresponding nitronederivative 2 (R¹ =3,4--Cl₂), and treating the latter with 4-chlorophenylallyl ether (3, R² =4--Cl). The resulting cis-and trans-diastereomericmixture of compound 4 (R¹ =3,4--Cl₂, R² =4--Cl) wasflash-chromatographed on neutral silica gel using a 98:2 by volumemixture of chloroform and methanol as eluent.

Isomer A has a melting point of 149°-151° C. (ethyl acetate).

Anal. Calcd for C₂₁ H₂₀ Cl₃ N₃ O₂ : C, 55.71; H, 4.45; N, 9.28; Cl,23.49. Found: C, 55.65; H, 4.50; N, 9.21; Cl, 23.61.

EXAMPLE 75-Phenoxymethyl-3-phenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine(4, R¹ =R² =H)

Compound 4 (R¹ =R² =H) was obtained by a procedure similar to thatdescribed in Example 1 by reacting 2-(1H-imidazol-1-yl)acetophenone (1,R¹ =H) with N-methylhydroxylamine hydrochloride to form thecorresponding nitrone derivative 2 (R¹ =H), and treating the latter withphenyl allyl ether (3, R² =H). The resulting cis- andtrans-diastereomeric mixture of compound 4 (R¹ =R² =H) wasflashchromatographed on neutral silica gel using a 98:2 by volumemixture of chloroform and methanol as eluent.

Isomer A has a melting point of 107°-109° C. (ethyl acetate).

Isomer B has a melting point of 165°-168° C. (isopropanol).

EXAMPLE 85-(3-(Trifluoromethyl)phenoxymethyl)-3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine(4, R¹ =4--Cl, R² =3--CF₃)

Compound 4 (R¹ =4--Cl, R² =3--CF₃) was obtained by a procedure similarto that described in Example 1 by reacting2-(1H-imidazol-1-yl)-4'-chloroacetophenone (1, R¹ =4--Cl) withN-methylhydroxylamine hydrochloride to form the corresponding nitronederivative 2 (R¹ =4--Cl), and treating the latter with3-(trifluoromethyl)phenyl allyl ether (3, R² =3--CF₃). The resultingcis- and trans-diastereomeric mixture of compound 4 (R¹ =4--Cl, R²=3--CF₃) was flash-chromatographed on neutral silica gel using a 98:2 byvolume mixture of dichloromethane and methanol as eluent.

Isomer A has a melting point of 80°-83° C. (benzene).

Anal. Calcd for C₂₂ H₂₁ N₃ O₂ ClF₃ : C, 58.48; H, 4.68; N, 9.30; Cl,7.85; F, 12.61. Found: C, 58.78; H, 4.60; N, 9.01; Cl, 7.84; F, 12.42.

EXAMPLE 95-(4-Methoxyphenoxymethyl)-3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine(4, R¹ =4--Cl, R² =4--OCH₃)

Compound 4 (R¹ =4--Cl, R² =4--OCH₃) was prepared by a procedure similarto that described in Example 1 by reacting2-(1H-imidazol-1-yl)-4'-chloroacetophenone (1, R¹ =4--Cl) withN-methylhydroxylamine hydrochloride to form the corresponding nitronederivative 2 (R¹ =4--Cl), and treating the latter with 4-methoxyphenylally either (3, R² =4--OCH₃). The resulting cis- andtrans-diastereomeric mixture of compound 4 (R¹ =4--Cl, R² =4--CH₃) wasflash-chromatographed on neutral silica gel using a 98:2 by volumemixture of dichloromethane and methanol as eluent.

Isomer A has a melting point of 140°-145° C. (ethyl acetate).

Anal. Calcd for C₂₂ H₂₄ N₃ O₃ Cl: C, 63.84; H, 5.84; N, 10.15; Cl, 8.57.Found: C, 64.16; H, 5.95; N, 10.16; Cl, 8.60.

EXAMPLE 105-(4-Methylphenoxymethyl)-3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine(4, R¹ =4--Cl, R² =4--CH₃)

Compound 4 (R¹ =4--Cl, R² =4--CH₃) was prepared by a procedure similarto that described in Example 1 by reacting2-(1H-imidazol-1-yl)-4'-chloroacetophenone (1, R¹ =4--Cl) withN-methylhydroxylamine hydrochloride to form the corresponding nitronederivative 2 (R¹ =4--Cl), and treating and latter with 4-methylphenylallyl ether (3, R² =4--CH₃). The resulting cis- and trans-diastereomericmixture of compound 4 (R¹ =4--Cl, R² =4--CH₃) was flash-chromatographedon neutral silica gel using a 98:2 by volume mixture of dichloromethaneand methanol as eluent.

Isomer A has a melting point of 115°-123° C. (ethyl acetate).

Isomer B has a melting point of 111°-134° C. (ethyl acetate).

Anal. Calcd for C₂₂ H₂₄ ClN₃ O₂ : C, 66.41; H, 6.08; N, 10.56; Cl, 8.91.Found C, 65.70; H, 6.15; N, 10.35; Cl, 9.10.

EXAMPLE 115-(2,5-Dichlorophenoxymethyl)-3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine(4, R¹ =4--Cl, R² =2,6--Cl₂)

Compound 4 (R¹ =4--Cl, R² =2,6--Cl₂) was made by a procedure similar tothat described in Example 1 by reacting2-(1H-imidazol-1-yl)-4'-chloroacetophenone (1, R¹ =4--Cl) withN-methylhydroxylamine hydrochloride to form the corresponding nitronederivative 2 (R¹ =4--Cl), and treating the latter with2,6-dichlorophenyl allyl ether (3, R² =2,6--Cl₂). The resulting cis- andtrans-diastereomeric mixture of compound 4 (R¹ =4--Cl, R² =2,6--Cl₂) wasflash-chromatographed on neutral silica gel using a 95:5 by volumemixture of dichloromethane and methanol as eluent.

Isomer A has a melting point of 144°-48° C. (ethyl acetate).

Anal. Calcd for C₂₁ H₂₀ N₃ O₂ Cl₃ : C,55.71; H, 4.45; N, 92.8; Cl,23.49. Found: C, 55.72; H, 4.58; N, 9.22; Cl, 23.14.

EXAMPLE 125-(2,4-Dichlorophenoxymethyl)-3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine(4, R¹ =4--Cl, R² =2,4--Cl₂)

Compound 4 (R¹ =4--Cl, R² =2,4--Cl₂) was obtained by a procedure similarto that described in Example 1 by reacting2-(1H-imidazol-1-yl)-4'-chloroacetophenone (1, R¹ =4--Cl) withN-methylhydroxylamine hydrochloride to form the corresponding nitronederivative 2 (R¹ =4--Cl), and treating the latter with2,4-dichlorophenyl allyl ether (3, R² =2,4--Cl₂). The resulting cis- andtrans-diastereomeric mixture of compound 4 (R¹ =4--Cl, R² =2,4--Cl₂) wasflash-chromatographed on neutral silica gel using ethyl acetate aseluent.

Isomer A has a melting point of 145°-148° C. (ethyl acetate).

Anal. Calcd for C₂₁ H₂₀ N₃ O₂ Cl₃ : C, 55.71; H, 4.45; N, 9.28; Cl,23.49. Found C, 55.55; H, 4.51; N, 9.18; Cl, 23.32.

EXAMPLE 135-(2-Nitrophenoxymethyl)-3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine(4, R¹ =4--Cl, R² =2--NO₂)

Compound 4 (R¹ =4--Cl, R² =2--NO₂) was made by a procedure similar tothat described in Example 1 by reacting2-(1H-imidazol-1-yl)-4'-chloroacetophenone (1, R¹ =4--Cl) withN-methylhydroxylamine hydrochloride to form the corresponding nitronederivative 2 (R¹ =4--Cl) and treating the latter with 2-nitrophenylallyl ether (3, R² =2--NO₂). The resulting cis- and trans-diastereomericmixture of compound 4 (R¹ =4--Cl, R² =2--NO₂) was flash-chromatographedon neutral silica gel using a 98:2 by volume mixture of dichloromethaneand methanol as eluent.

Isomer A has a melting point of 135°-138° C. (ethyl acetate).

Anal. Calcd for C₂₁ H₂₁ N₄ O₄ Cl: C, 58.81; H, 4.94; N, 13.06; Cl, 8.27.Found: C, 58.88; H, 4.98; N, 13.12; Cl, 8.38.

EXAMPLE 145-(4-Fluorophenoxymethyl)-3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine(4, R¹ =4--Cl, R² =4--F)

Compound 4 (R¹ =4--Cl, R² =4--F) was obtained by a procedure similar tothat described in Example 1 by reacting2-(1H-imidazol-1-yl)-4'-chloroacetophenone (1, R¹ =4--Cl) withN-methylhydroxylamine hydrochloride to form the corresponding nitronederivative 2 (R¹ =4--Cl), and treating and latter with 4-fluorophenylallyl ether (3, R² =4--F). The resulting cis- and trans-diastereomericmixture of compound 4 (R¹ =4--Cl, R² =4--F) was flash-chromatographed onneutral silica gel using a 98:2 by volume mixture of dichloromethane andmethanol as eluent.

Isomer A has a melting point of 121°-126° C. (ethyl acetate).

Calcd for C₂₁ H₂₁ N₃ O₂ ClF: C, 62.76; H, 5.27; N, 10.46; Cl, 8.82; F,4.73. Found: C, 62.72; H, 5.26; N, 10.43; Cl, 8.66; F, 4.68.

EXAMPLE 155-(4-Chlorophenoxy)methyl-3-(4-chloro-3-methylphenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazoldine(4,R¹ =4--Cl, 3--CH₃, R² =4--Cl).

Compound 4 (R¹ =4--Cl, 3--CH₃, R² =4--Cl) was made by a proceduresimilar to that described in Example 1 by reacting2-(1H-imidazol-1-yl)-4'-chloro-3'methylacetophenone (1, R¹ =4--Cl,3--CH₃) with N-methylhydroxylamine hydrochloride to form thecorresponding nitrone derivative 2 (R¹ =4--Cl, 3--CH₃), and treating thelatter with 4-chlorophenyl allyl ether (3, R² =4--Cl). The resultingcis- and trans-diastereomeric mixture of compound 4 (R¹ =4--Cl, 3--CH₃,R² =4--Cl) was flash-chromatographed on neutral silica gel using a 98:2by volume mixture of chloroform and methanol as eluent.

Isomer A has a melting point of 142°-146° C. (ethyl acetate).

Anal. Calcd for C₂₂ H₂₃ Cl₂ N₃ O₂ : C, 61.12; H, 5.36; N, 9.72; Cl,16.40. Found: C, 61.08; H, 5.45; N, 9.72; Cl, 16.34.

EXAMPLE 165-(4-Chlorophenoxy)methyl-3-(1H-imidazol-1-ylmethyl)-3-(3-methoxyphenyl)-2-methylisoxazolidine(4, R¹ =3--CH₃ O, R² =4--Cl)

Compound 4 (R¹ =3--CH₃ O, R² =4--Cl) was made by a procedure similar tothat described in Example 1 by reacting2-(1H-imidazol-1-yl)-3'-methoxyacetophenone (1, R¹ =3--CH₃ O) withN-methylhydroxylamine hydrochloride to form the corresponding nitronederivative 2 (R¹ =3--CH₃ O) and treating the latter with 4-chlorophenylallyl ether (3, R² =4--Cl). The resulting cis- and trans-diastereomericmixture of compound 4 (R¹ =3--CH₃ O, R² =4--Cl) wasflash-chromatographed on neutral silica gel using a 98:2 by volumemixture of chloroform and methanol as eluent.

Isomer A has a melting point of 92°-95° C. (ethyl ether).

Anal. Calcd for C₂₂ H₂₄ ClN₃ O₃ : C, 63.84; H, 5.84; N, 10.15; Cl, 8.57.Found: C, 63.61; H, 5.90; N, 10.14; Cl, 8.55.

EXAMPLE 175-(4-Chlorophenoxy)methyl-3-(1H-imidazol-1-ylmethyl)-2-methyl-3-(3-methylphenyl)isoxazolidine (4, R¹ =3--CH₃, R² =4--Cl)

Compound 4 (R¹ =3--CH₃, R² =4--Cl) was made by a procedure similar tothat described in Example 1 by reacting2-(1H-imidazol-1-yl)-3'-methylacetophenone (1, R¹ =3--CH₃) withN-methylhydroxylamine hydrochloride to form the corresponding nitronederivative 2 (R¹ =3--CH₃), and treating the latter with 4-chlorophenylallyl ether (3, R² =4--Cl). The resulting cis- and trans-diastereomericmixture of compound 4 (R¹ =3--CH₃, R² =4--Cl) was flash-chromatographedon neutral silica gel using a 99:1 by volume mixture of chloroform andmethanol as eluant.

Isomer A has a melting point of 122°-124° C. (ethyl acetate).

Anal. Calcd. for C₂₂ H₂₄ ClN₃ O₂ : C, 66.41; H, 6.08; N, 10.56; Cl,8.91. Found: C, 66.45; H, 6.14; N, 10.63; Cl, 9.09.

EXAMPLE 185-[2-(4-Chlorophenoxy)ethyl]-3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine(6, R¹ =R² =4--Cl, n=2)

Compound 6 (R¹ =4--Cl, R² =4--Cl, n=2) was prepared by a proceduresimilar to that described in Example 1 by reacting2-(1H-imidazol-1-yl)-4'-chloroacetophenone (1, R¹ =4--Cl) withN-methylhydroxylamine hydrochloride to form the corresponding nitronederivative 2 (R¹ =4--Cl), and treating the latter with1-(3-butenyloxo)-4-chlorobenzene (5, R² =4--Cl, n=2). The resulting cis-and trans-diastereomeric mixture of compound 6 (R¹ =4--Cl, R² =4--Cl,n=2) was flash-chromatographed on neutral silica gel using a 98:2 byvolume mixture of chloroform and methanol as eluent.

Isomer A has a melting point of 103°-105° C. (ethyl acetate).

Anal. Calcd for C₂₂ H₂₃ Cl₂ N₃ O₂ : C, 61.12; H, 5.36; N, 9.72; Cl,16.40. Found: C, 61.08; H, 5.44; N, 9.64; Cl, 16.50.

EXAMPLE 195-[3-(4-Chlorophenoxy)propyl]-3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine(6, R¹ =R² =4--Cl, n=3)

Compound 6 (R¹ =R² =4--Cl, n=3) was prepared by a procedure similar tothat described in Example 1 by reacting2-(1H-imidazol-1-yl)-4'-chloroacetophenone (1, R=4--Cl) withN-methylhydroxylamine hydrochloride to form the corresponding nitronederivative 2 (R¹ =4--Cl), and treating the latter with1-(4-pentenyloxy)-4-chlorobenzene (5, R² =4--Cl, n=3). The resultingcis- and trans-diasteriomeric mixture of compound 6 (R¹ =R² =4--Cl, n=3)was flash-chromatographed on neutral silica gel using a 98:2 by volumemixture of chloroform and methanol as eluent.

Isomer A has a melting point of 118°-123° C. (ethyl acetate).

Anal. Calcd. for C₂₃ H₂₅ Cl₂ N₃ O₂ : C, 61.89; H, 5.65; N, 9.41; Cl,15.88. Found: C, 6.99; H, 5.71; N, 9.42; Cl, 15.47.

EXAMPLE 20 3-(4-Chlorophenyl)-5-[3-(4-fluorophenoxy)propyl]-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine(6, R¹ =4--Cl, R² =4--F, n=3)

Compound 6 of (R¹ =4--Cl, R² =4--F, n=3) was prepared by a proceduresimilar to that described in Example 1 by reacting2-(1H-imidazol-1-yl)-4'-chloroacetophenone (l, R¹ =4--Cl) withN-methylhydroxylamine hydrochloride to form the corresponding nitronederivative 2 (R¹ =4--Cl), and treating the latter with1-(4-pentenyloxy)-4-fluorobenzene (5, R² =4--F, n=3). The resulting cis-and trans-diastereomeric mixture of compound 6 (R¹ =4--Cl, R² =4--F,n=3) was flash-chromatographed on neutral silica gel using a 98:2 byvolume mixture of chloroform and methanol as eluent.

Isomer A has a melting point of 116°-120° C. (ethyl acetatehexane, 1:1by volume).

EXAMPLE 215-[3-(4-Fluorophenoxy)propyl]-3-(4-fluorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine(6, R¹ =R² =4--F, n=3)

Compound 6 (R¹ =R² =4--F, n=3) was prepared by a procedure similar tothat described in Example 1 by reacting2-(1H-imidazol-1-yl)-4'-fluoroacetophenone (1, R¹ =4--F) withN-methylhydroxylamine hydrochloride to form the corresponding nitronederivative 2 (R¹ =4--F), and treating the latter with1-(4-pentenyloxy)-4-fluorobenzene (5, R² =4--F, n=3). The resulting cis-and trans-diastereomeric mixture of compound 6 (R¹ =R² =4--F, n=3) wasflash-chromatographed on neutral silica gel using a 98:2 by volumemixture of chloroform and methanol as eluent.

Isomer A has a melting point of 96°-100° C. (ethyl acetatehexane, 1:1 byvolume).

EXAMPLE 225-[(4-Fluorophenoxy)methyl]-3-(1H-imidazol-1-ylmethyl)-2-methyl-3-phenylisoxazolidine(4, R¹ =H, R² =4--F)

Compound 4 (R¹ =H, R² =4--F) was made by a procedure similar to thatdescribed in Example 1 by reacting 2-(1H-imidazol-1-yl)acetophenone (1,R¹ =H) with N-methylhydroxylamine hydrochloride to form thecorresponding nitrone derivative 2 (R¹ =H), and treating the latter with4-fluorophenyl allyl ether (3, R² =4--F). The resulting cis- andtrans-diastereomeric mixture of compound 4 (R¹ =H, R² =4--F) wasflash-chromatographed on neutral silica gel using ethyl acetate aseluent.

Isomer A has a melting point of 115°-117° C. (ethyl acetate).

Anal. Calcd for C₂₁ H₂₂ FN₃ O₂ : C, 68.65; H, 6.04; N, 11.44; F, 5.17.Found: C, 68.54; H, 6.16; N, 11.41; F, 5.15.

Isomer B has a melting point of 111°-115° C. (ethyl acetate).

Anal. Calcd for C₂₁ H₂₂ FN₃ O₂ : C, 68.65; H, 6.04; N, 11.44; F, 5.17.Found: C, 69.03; H, 6.13; N, 11.38; F, 5.22.

EXAMPLE 235-[(4-Chloro-3-methylphenoxy)methyl]-3-(1H-imidazol-1-ylmethyl)-2-methyl-3-phenylisoxazolidine(4, R¹ =H, R² =4--Cl, 3--CH₃)

Compound 4 (R¹ =H, R² =4--Cl, 3--CH₃) was prepared by a method similarto that described in Example 1 by reacting2-(1H-imidazol-1-yl)acetophenone (1,R¹ =H) with N-methylhydroxylaminehydrochloride to form the corresponding nitrone derivative 2 (R¹ =H),and treating the latter with 4-chloro-3-methylphenyl allyl ether (3, R²=4--Cl, 3--CH₃). The resulting cis- and trans-diastereomeric mixture ofcompound 4 (R¹ =H, R² =4--Cl, 3--CH₃) was flash-chromatographed onneutral silica gel using a 98:2 by volume mixture of chloroform andmethanol as eluent.

Isomer A a has melting point of 110°-120° C. (ethyl acetate).

Anal. Calcd for C₂₂ H₂₄ ClN₃ O₂ : C, 66.41; H, 6.08; N, 10.52; Cl, 8.91.Found: C, 66.38; H, 6.19; N, 10.46; Cl, 8.87.

EXAMPLE 243-(4-Fluorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methyl-5-(phenoxymethyl)isoxazolidine(4, R¹ =4--F, R² =H)

Compound 4 (R¹ =4--F, R² =H) was made by a procedure similar to thatdescribed in Example 1 by reacting4'-fluoro-2-(1H-imidazol-1-yl)acetophenone (1, R¹ =4--F) withN-methylhydroxylamine hydrochloride to form the corresponding nitronederivative 2 (R¹ =4--F), and treating the latter with phenyl allyl ether(3, R² =H). The resulting cis- and trans-diastereomeric mixture ofcompound 4 (R¹ =4--F, R² =H) was flash-chromatographed on neutral silicagel using a 98:2 by volume mixture of chloroform and methanol.

Isomer A has a melting point of 164°-166° C. (isopropanol).

Anal. Calcd for C₂₁ H₂₂ FN₃ O₂ : C, 68.65; H, 6.04; N, 11.44; F, 5.17.Found: C, 68.62; H, 5.96; N, 11.37; F, 5.12.

EXAMPLE 255-[(4-Fluorophenoxy)methyl]-3-(4-fluorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine(4, R¹ =R² =4--F)

Compound 4 (R¹ =R² =4--F) was made by a procedure similar to thatdescribed in Example 1 by reacting 4'-fluoro-2-(1H-imidazol-1-yl)acetophenone (1, R¹ =4--F) with N-methylhydroxylamine hydrochloride toform the corresponding nitrone derivative 2 (R¹ =4--F), and treating thelatter with 4-fluorophenyl allyl ether (3, R² =4--F). The resulting cis-and trans-diastereomeric mixture of compound 4 (R¹ =R² =4--F) wasflash-chromatographed on neutral silica gel using ethyl acetate as theeluent.

Isomer A has a melting point 141°-143° C. (ethyl acetate).

Anal. Calcd for C₂₁ H₂₁ F₂ N₃ O₂ : C, 65.44; H, 5.49; N, 10.90; F, 9.86.Found: C, 65.84; H, 5.38; N, 10.88; F, 9.55.

EXAMPLE 263-(1H-Imidazol-1-ylmethyl)-5-[(4-methoxyphenoxy)methyl]-3-(4-methoxyphenyl)-2-methylisoxazolidine(4, R¹ =R² =4--OCH₃)

Compound 4 (R¹ =R² =4--OCH₃) was made by a procedure similar to thatdescribed in Example 1 by reacting2-(1H-imidazol-1-yl)-4'-methoxyacetophenone (1, R¹ =4--OCH₃) withN-methylhydroxylamine hydrochloride to form the corresponding nitronederivative 2 (R¹ =4--OCH₃), and treating the latter with 4-methoxyphenylallyl ether (3, R² =4--OCH₃). The resulting cis- andtrans-diastereomeric mixture of compound 4 (R¹ =R² =4--OCH₃) wasflash-chromatographed on neutral silica gel using a 98:2 by volumemixture of methylene chloride and methanol as eluent.

Isomer A has a melting point of 96°-101° C. (ethyl acetate).

Anal. Calcd for C₂ H₂₇ N₃ O₄ : C, 67.46; H, 6.65; N, 10.26. Found C,67.43; H, 6.64; N, 10.20.

EXAMPLE 275-[(4-Acetamidophenoxy)methyl]-3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine(4, R¹ =4--Cl, R² =NHAc)

Compound 4 (R¹ =4--Cl, R² =NHAc) was prepared by a method similar tothat described in Example 1 by reacting 4'-chloro-2-(1H-imidazol-1-yl)acetophenone (1, R¹ =4--Cl) with N-methylhydroxylamine hydrochloride toform the corresponding nitrone derivative 2 (R¹ =4--Cl), and treatingthe latter with 4-acetamidophenyl allyl ether (3, R² =4-NHAc). Theresulting cis- and trans-diastereomeric mixture of compound 4 (R¹=4--Cl, R² =4-NHAc) was flash-chromatographed on neutral silica gelusing a 98:2 by volume mixture of chloroform and methanol as eluent.

Isomer A has a melting point of 181°-186° C. (ethyl acetate).

Anal. Calcd for C₂₃ H₂₅ C1N₄ O₃ : C, 62.65; H, 5.72; N, 12.71; Cl, 8.04.Found: C, 62.52; H, 5.76; N, 12.58; Cl, 8.09.

EXAMPLE 28 Salts of5-(4-Chlorophenoxymethyl)-3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine(4, R¹ =R² =4--Cl)

Salts of the title compound 4 were prepared by dissolving the compoundin a 10:1 by volume mixture of ethanol and the appropriate concentratedacid, evaporating the solvent and then recrystallizing the crude saltfrom methanol-ether (1:3 by volume in the case of the HC1 salt), andethanol in the case of the HNO₃ salt.

Isomer A·2HC1 has a melting point of 170°-183° C.

Anal. Calcd for C₂₁ H₂₃ Cl₄ N₃ O₂ : C, 51.35; H, 4.72; N, 8.55; Cl,28.87. Found, C, 51.45; H, 4.84; N, 8.50; Cl, 27.72.

Isomer A·HNO₃ has a melting point of 165°-167° C.

Anal. Calcd for C₂₁ H₂₂ Cl₂ N₄ O₅ : C, 52.40; H, 4.61; N, 11.67; Cl,14.73. Found: C, 52.51; H, 4.70; N, 11.67; Cl, 14.84.

Salts with other acids and salts of other compounds of the invention canbe prepared in a similar manner.

We claim:
 1. A compound of the formula: ##STR4## or a pharmaceuticallyacceptable acid addition salt thereof, in the form of their enantiomersor mixtures of their enantiomers including diastereoisomeric pairs ofsuch enantiomers, wherein;a=1 or 2, b=1 or 2, R¹ is selected fromhydrogen, lower alkyl, lower alkoxy, halogen, and combinations thereof,provided that the ortho position is hydrogen, R² is selected fromhydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, nitro,acetamido, and combinations thereof, and the alkyl moiety (CH₂)nrepresents a branched or unbranched chain were n=1 to
 8. 2. The compoundof claim 1 wherein the compound is5-(4-chlorophenoxymethyl)-3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine.3. The compound of claim 1 wherein the compound is5-(4-chlorophenoxymethyl)-3-(4-methoxyphenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine.4. The compound of claim 1 wherin the compound is5-(4-chlorophenoxymethyl)-3-(4-methylphenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine.5. The compound of claim 1 wherein the compound is5-(4-chlorophenoxymethyl)-3-(4-fluorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine.6. The compound of claim 1 wherein the compound is5-(4-chlorophenoxymethyl)-3-phenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine.7. The compound of claim 1 wherein the compound is5-(4-chlorophenoxymethyl)-3-(3,4-dichlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine.8. The compound of claim 1 wherein the compound is5-phenoxymethyl-3-phenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine.9. The compound of claim 1 wherein the compound is5-[3-(trifluoromethyl)phenoxymethyl]-3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine.10. The compound of claim 1 wherein the compound is5-(4-methoxyphenoxymethyl)-3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine.11. The compound of claim 1 wherein the compound is5-(4-methylphenoxymethyl)-3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine.12. The compound of claim 1 wherein the compound is5-(2,6-dichlorophenoxymethyl)-3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine.13. The compound of claim 1 wherein the compound is5-(2,4-dichlorophenoxymethyl)-3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine.14. The compound of claim 1 wherein the compound is5-(2-nitrophenoxymethyl)-3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethy)-2-methylisoxazolidine.15. The compound of claim 1 wherein the compound is5-(4-fluorophenoxymethyl)-3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine.16. The compound of claim 1 wherein the compound is5-(4-chlorophenoxy)methyl-3-(4-chloro-3-methylphenyl)-3-1H-imidazol-1-yl-methyl)-2-methylisoxazolidine.17. The compound of claim 1 wherein the compound is5-(4-chlorophenoxy)methyl-3-(1H-imidazol-1-ylmethyl)-3-(3-methoxyphenyl)-2-methylisoxazolidine.18. The compound of claim 1 wherein the compound is5-(4-chlorophenoxy)methyl-3-(1H-imidazol-1-ylmethyl)-2-methyl-3-(3-methylphenyl)isoxazolidine.19. The compound of claim 1 wherein the compound is5-[2-(4-chlorophenoxy)ethyl]-3-(4-chlorophenyl)-3H-imidazol-1-ylmethyl)-2-methylisoxazolidine.20. The compound of claim 1 wherein the compound is5-[3-(4-chlorophenoxy)propyl]-3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine.21. The compound of claim 1 wherein the compound is3-(4-chlorophenyl)-5-[3-(4-fluorophenoxy)propyl]-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine.22. The compound of claim 1 wherein the compound is5-[3-(4-fluorophenoxy)propyl]-3-(4-fluorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine.23. The compound of claim 1 wherein the compound is5-[(4-fluorophenoxy)methyl]-3-(1H-imidazol-1-ylmethyl)-2-methyl-3-phenylisoxazolidine.24. The compound of claim 1 wherein the compound is5-[(4-chloro-3-methylphenoxy)methyl]-3-(1H-imidazol-1-ylmethyl)-2-methyl-3-phenylisoxazolidine.25. The compound of claim 1 wherein the compound is3-(4-fluorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methyl-5-(phenoxymethyl)isoxazolidine.26. The compound of claim 1 wherein the compound is5-[(4-fluorophenoxy)methyl]-3-(4-fluorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine.27. The compound of claim 1 wherein the compound is3-(1H-imidazol-1-ylmethyl)-5-[(4-methoxyphenoxy)methyl]-3-(4-methoxyphenyl)-2-methylisoxazolidine.28. The compound of claim 1 wherein the compound is5-[(4-acetamidophenoxy)methyl]-3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine.29. The compound of claim 1 wherein the compound is a diastereoisomericpair of enantiomers.